Specific Aim. Prostate cancer (PCA) is a molecularly heterogeneous disease with a varied clinical spectrum ranging from indolent to highly aggressive. One late manifestation of PCA is progression to a neuroendocrine phenotype, which is universally lethal with an average survival of less than one year. It is estimated that 30% of late stage PCA transforms to neuroendocrine prostate cancer (NEPC), and potentially selected for or accelerated by the use of androgen deprivation therapies. With the introduction of more potent hormonal therapy into the clinical arena (e.g., Abiraterone, MDV3100), the incidence of NEPC is expected to escalate. We have generated preliminary data from Whole Genome DNA and RNA Sequencing leading us to hypothesize that NEPC arises from adenocarcinoma (AdCa) and that telltale molecular events determine a progression from hormone nave AdCa to lethal NEPC. Therefore, we propose 3 Specific Aims to elucidate the key molecular drivers of NEPC. Specific Aim 1: Define Somatic Copy Number Alterations Associated with the Emergence of NEPC. The working hypothesis of this Aim is that there are recurrent somatic copy number alterations (SCNA) associated with NEPC detectable prior to the development of neuroendocrine de-differentiation. At the conclusion of this Aim, we will nominate up to 20 genes from SCNA loci that are recurrent in NEPC and less common in AdCa with transcriptional support suggesting that these are gain of function (oncogenes) or loss of function (tumor suppressor) genes. Specific Aim 2: Determine Spectrum of Mutations Observed in NEPC. The working hypothesis of this Aim is that there are specific driving mutations that characterize NEPC. At the end of this Aim, we anticipate that a subset of these mutations and rearrangements contribute to neuroendocrine de-differentiation. We anticipate nominating up to 20 mutations that will be appropriate for further molecular functional evaluation. Specific Aim 3 Determine the Functional Activity of NEPC Genes. The working hypothesis of this Aim is that alterations in a subset of the genes nominated in Aims 1-2 are gain or loss of function mutations. At the conclusion of this Aim we will have nominated up to 5 functionally active genes that are present in NEPC and a subset of AdCa. We will immediately follow up on these genes using xenograft models as part of another funded grant (no animal experiments are proposed in this application). We believe that the proposed studies will allow us new insight into a highly aggressive form of PCA.